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Upper airways and neonatal respiration
Respiratory Physiology & Neurobiology 149 (2005) 131–141
Upper airways and neonatal respiration Jean-Paul Praud a,∗ , Philippe Reix b a
Neonatal Respiratory Research Unit, Departments of Pediatrics and Physiology, Faculty of Medicine, Universit´e de Sherbrooke, Sherbrooke, Que., Canada J1H 5N4 b Department of Pediatrics, Universit´ e de Lyon, France Accepted 30 April 2005
Abstract The upper airways exert an important influence on breathing from the fetal period onward. This review focuses on recent results obtained in the newborn, particularly on laryngeal function in the lamb. Cumulated data can be summarized as follows. Firstly, upper airway closure, either at the pharyngeal or laryngeal level, is now known to occur during central apneas. By maintaining a high apneic lung volume throughout central apneas, active laryngeal closure decreases the magnitude of post-apneic desaturation. Secondly, reflexes originating from laryngeal mucosal receptors, such as laryngeal chemoreflexes and non-nutritive swallowing, are of crucial importance within the context of preterm birth, postnatal maturation, neonatal apneas and apparent life-threatening events/sudden infant death syndrome. While laryngeal chemoreflexes appear to be mature and confer an efficient protection against aspiration in the full-term healthy newborn, they can be responsible for prolonged apneas and bradycardias in the immature preterm newborn. In regard to non-nutritive swallowing, the absence of swallowing activity during apneas in periodic breathing during quiet sleep as well as the presence of bursts of swallows with apneas in active sleep remain to be explained. Forthcoming studies will have to further delineate the impact of common clinical conditions, such as cigarette smoke exposure and/or viral respiratory infection on laryngeal chemoreflexes and non-nutritive swallowing. Better knowledge on the importance of the upper airways in neonatal respiration will ultimately aid in designing clinical applications for the understanding and treatment of severe, pathological respiratory conditions of the newborn. © 2005 Elsevier B.V. All rights reserved. Keywords: Larynx; Apnea; Sleep; Lamb
1. Introduction The upper airways, consisting of the nose, mouth, pharynx and larynx, are an essential component of the ∗ Corresponding author. Tel.: +1 819 346 1110x14851; fax: +1 819 564 5215. E-mail address: [email protected] (J.-P. Praud).
1569-9048/$ – see front matter © 2005 Elsevier B.V. All rights reserved. doi:10.1016/j.resp.2005.04.020
breathing apparatus and exert an important influence on breathing from the fetal period onward. In addition to participating in fetal lung growth, in the establishment and maintenance of optimal end expiratory lung volume at birth and in the decrease in upper airway inspiratory resistance during air breathing, they are also involved in reflex mechanisms such as nutritive and non-nutritive swallowing and cough. A number of
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pathological conditions, such as anatomical abnormalities of the cervico-facial region or central neurological immaturity due to preterm birth, can lead to upper airway dysfunction and obstructed breathing in the newborn. Furthermore, neural immaturity in the newborn is often responsible for reflexes originating from the nose or the laryngeal region, which are inhibitory to cardio-respiratory rhythm. This short review will focus on recent findings on laryngeal function, in relation to neonatal apneas, laryngeal chemoreflexes, and coordination between non-nutritive swallowing and respiration. Importance of these findings is ultimately related to their clinical applications in the understanding and treatment of severe, pathological respiratory conditions of the newborn.
2. Upper airways and apneas in the newborn 2.1. Neonatal apneas Apneas, defined as a breathing pause corresponding to at least “two missed breaths”, are very frequent in the neonatal period, especially in the preterm newborn. Short isolated apneas without bradycardia or decline in oxygenation are especially frequent following sighs and with body movements or arousals. Apneas accompanied by bradycardia or a significant decline in oxygenation, regardless of apnea duration, are regarded as pathological and basically the only apneas of real importance for the clinician. As a whole, neonatal apneas are more common, longer and more frequently associated with severe hypoxemia and bradycardia during rapid eye movement sleep (REM sleep). Three types of apneas have been reported in newborn humans: central, obstructive and mixed. Central apneas occur with greater frequency in nonREM sleep, often as periodic breathing, which is defined as the alternation of central apneas and regular breathing. Apneas become predominantly mixed when they are longer than 10 s. Purely obstructive apneas are much less frequent (Baird, 2004; Milner and Greenough, 2004). Consequences of neonatal apneas on blood gases (hypoxia) and heart rate (bradycardia) can be immediately life-threatening due to severe cerebral hypoxia, especially in preterm infants, and carry the potential of lifelong neurological sequellae, namely
cerebral palsy. While many questions on the mechanisms responsible for controlling neonatal apneas remain unresolved, available data suggest an important role for the upper airways, even during central apneas. 2.2. Upper airways and neonatal apneas Upper airways are of course an essential component of mixed/obstructive apneas. Aside from conditions such as congenital abnormalities (e.g., cervico-facial malformations, laryngomalacia, vocal cord paralysis), it is generally acknowledged that two different mechanisms are involved in mixed/obstructive apneas in the newborn. The most frequently recognized mechanism is passive pharyngeal collapse during inspiration (Milner and Greenough, 2004), which is favored by conditions such as cervical flexion, nose obstruction or lack of pharyngeal muscle-diaphragm coordination secondary to central neural immaturity/abnormalities. In addition, it is well recognized that active glottal closure can occur as part of the laryngeal chemoreflexes, which are triggered by stimulation of laryngeal mucosal receptors by liquids. Laryngeal chemoreflexes in the immature newborn include central or mixed apneas, among other reflexes, and are observed in response to pooling of salivary or respiratory secretions, gastro-esophageal reflux and during feeding (Thach, 2001). Although less often recognized, upper airway closure during central apneas now appears to be frequent in the newborn mammal. Again, passive pharyngeal collapse has been shown to be present during central apneas, both isolated and during periodic breathing epochs (see review, Milner and Greenough, 2004). Several arguments also support the presence of frequent active glottal closure during central apneas in the human newborn. Indeed, endoscopic observation of sustained glottal closure during central apneas has been shown during apneas of prematurity, both isolated and during periodic breathing (Milner and Greenough, 2004), a fact frequently reported by clinicians at laryngoscopy. Several animal studies in the 1980s lent further support to the concept of frequent active glottal closure during central apneas in the newborn mammal, including lambs (Harding, 1986), dog pups (England, 1985) and newborn opossums (Farber, 1972). However, given the paucity of spontaneous apneas observed in newborn mammals born at term
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and the difficulty of documenting glottal closure in human infants, the importance of these observations was not fully recognized. Data from our laboratory obtained in non-sedated lambs have established that the above observations were indeed not just anecdotal. The reader is referred to previous publications from our group for methodological details on glottal muscle EMG recording and methods to induce central apneas in full-term lambs (Renolleau et al., 1999; Fortier et al., 2003). First, in full-term lambs, we were able to show that continuous glottal constrictor EMG (recorded with wire electrodes surgically implanted in the thyroarytenoid muscle) is consistently observed throughout artificiallyinduced central apneas, both isolated and during periodic breathing epochs. Complete active glottal closure was confirmed by recording positive translaryngeal pressure with continuous glottal constrictor EMG throughout induced apneas. In addition, while tracheal pressure was continuously above atmospheric pressure, observation that supra-glottal pressure was consistently atmospheric throughout induced central apneas revealed that the pharynx was not (completely) closed during apneas (Fortier et al., 2003) (Fig. 1). However, in order to establish their physiological rele-
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vance, the above findings needed to be replicated during spontaneous apneas. At first, this latter approach was prevented by the very few spontaneous apneas actually experienced by full-term lambs, even while moving freely, using a custom-designed radio telemetry system (Renolleau et al., 1999). A suitable animal model of neonatal apneas was finally achieved with lambs born prematurely between 129 and 132 days of gestation (term = 147 days) (Renolleau et al., 1999). Since then, characterization of this unique model from 133 to 152 days of postconceptional age has shown that cardiorespiratory immaturity is indeed present. This is manifested by a decrease in the cardio-respiratory response to hypercapnia and hypoxia, as compared to term lambs (unpublished observations), and by numerous spontaneous central apneas, both isolated and within periodic breathing epochs, leading to repetitive drops in oxyhemoglobin saturation, as measured by pulse oximetry (SpO2 ) (Renolleau et al., 1999; Reix et al., 2003a,b). Continuous glottal constrictor EMG was observed in 88% of these central apneas, both isolated and during periodic breathing, ranging from 75% in REM sleep to more than 90% in nonREM sleep and quiet wakefulness. Furthermore, glottal constrictor EMG was consistently associated with positive subglottal pressure and
Fig. 1. Periodic breathing developing at return from a 15-min hypoxic run (FI O2 = 0.08) to room air breathing. TA: raw thyroarytenoid muscle (a glottal constrictor muscle) electrical activity (EMG); ʃTA: moving time averaged TA (time constant: 100 ms); Supra: supra-glottal pressure; Sub: sub-glottal pressure; Flow: nasal flow, inspiration upwards; Sum: variations of lung volume, assessed from respiratory inductance plethysmography.
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maintenance of a high apneic lung volume, i.e., inspiratory breath-holding, throughout spontaneous apneas (Renolleau et al., 1999; Reix et al., 2003a,b). More recently, glottal dilator muscle EMG was shown to be present during only 10–30% of central apneas (in both full-term and preterm lambs), mostly only during the last third of apneas (unpublished observations). Glottal dilator muscle EMG was also shown to be accompanied by a simultaneous decrease in apneic lung volume. 2.3. Consequences of glottal closure throughout neonatal central apneas Consequences of active glottal closure throughout central apneas can be theoretically either beneficial or deleterious and are not fully determined as of yet. Benefits are related to consequences of inspiratory breath-holding, i.e., maintenance of a high lung volume, maintenance of positive sub-glottal pressure and resumption of breathing with expiration. Maintenance of a high pulmonary volume during central apneas increases alveolar O2 stores and limits arterial O2 desaturation, despite absent lung ventilation (Reix et al., 2003a,b). In addition, maintenance of positive sub-glottal pressure likely increases lower airway stability and lung compliance whilst decreasing the tendency for atelectasis and further hypoxemic apnea. Finally, resumption of breathing with expiration can minimize aspiration of secretions, which may have accumulated in the hypopharynx during apnea. Conversely, while one can speculate on the deleterious effects of inspiratory breath-holding in newborns, the importance of such effects remains to be demonstrated. While breathing cessation in an inspiratory position could theoretically inhibit the next inspiration through the Hering–Breuer inhibitory reflex and thereby prolong apnea duration, this has not been supported by our findings (Reix et al., 2003a,b). Finally, while the return of inspiratory efforts despite on-going laryngeal closure (mixed apnea) has been observed in preterm lambs (Renolleau et al., 1999; Reix et al., 2003a,b), it remains a rare occurrence in this model. 2.4. Origin of active glottal closure during neonatal central apneas Interestingly, the above observations of active glottal closure with inspiratory breath-holding throughout
central apneas in newborn lambs have ontogenetic and phylogenetic correlations. From a phylogenetic standpoint, alternation of breathing movements and prolonged apneas, with the exchanger full of gas (i.e., inspiratory breath-holding with active glottal closure), is currently considered to represent the basic breathing pattern in air-breathing vertebrates. This primitivebreathing pattern can be observed to this day in lower vertebrates such as amphibians and aquatic reptiles, and is also present in diving mammals such as whales and seals, even while on land. From an ontogenetic standpoint, during late gestation, “fetal breathing” is present as alternating periods with diaphragm EMG bursts during REM sleep and prolonged “central apneas” with active glottal closure during nonREM sleep. Active glottal closure is responsible for positive pressure in the trachea, which, by distending the liquid-filled airways, is an important mechanism promoting prenatal lung growth. And although active glottal closure during central apneas is usually considered vestigial at most in non-diving adult mammals, it has been reported in adult humans during a few spontaneous central apneas (Insalaco et al., 1993). Finally, inspiratory breath-holding with active glottal closure is commonly observed throughout life with Valsalva maneuvers in conditions such as defecation, micturition, parturition and heavy load carrying. However, contrary to induced apneas in full-term lambs (Kianicka et al., 1998), Valsalva maneuvers are associated with forceful tonic abdominal muscle contraction throughout inspiratory breath-holding. Data in the literature on laryngeal control during apnea are scarce and unclear. Insofar as central mechanisms are concerned, the demonstration that stimulation of ␣2 adrenergic agonists induces tonic glottal constrictor EMG during central apneas in awake goats has led to speculation on the direct involvement of brainstem ␣2 adrenergic receptors in active glottal closure during apneas (Hedrick et al., 1998). This hypothesis still awaits confirmation. As for the effect of peripheral input, investigators have previously speculated that increased vagal afferent activity related to decreased lung volume is responsible for continuous glottal constrictor EMG during central apneas in full-term lambs (Harding, 1986). However, glottal constrictor EMG is still observed throughout induced central apneas in fullterm lambs, despite thoracic vagotomy (Praud et al., 1992) or maintenance of a high lung volume (Praud
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et al., 1996). These observations are also independent of the presence of laryngeal afferent activity, as shown after severing of both superior laryngeal nerves (Fortier et al., 2003). Glottal constrictor EMG is not modified either by various conditions of arterial PO2 or PCO2 (Praud et al., 1992, 1996; Fortier et al., 2003). This demonstrates that neither central nor peripheral chemoreceptor activity is the primary factor responsible for active glottal closure throughout central apneas in full-term lambs. Of interest, active glottal closure is also present throughout inspiratory breath-holding, alternating with gasps during anoxic gasping in lambs (Thuot et al., 2001). Since gasping respiration is speculated to originate from different brainstem centers than those implicating eupnea, such observations suggest that reciprocal inhibition between motoneurons driving glottal constrictor muscles and inspiratory bulbospinal neurons is a consistent feature despite varying respiratory control circumstances, including eupnea, apnea and gasping respiration. In summary, upper airway closure appears to be an important feature of neonatal apneas, including not only during obstructive/mixed apneas, but also during central apneas. Current evidence supports the view that both passive pharyngeal collapse and active glottal closure are involved. The presence of either of these mechanisms may depend on species differences or other, yet undefined, conditions. 3. Laryngeal chemoreflexes The laryngeal chemoreflexes (LCR) are triggered by the contact between liquids – either acid or with low chloride content – and receptors of the laryngeal mucosa in mammals. In a mature organism, liquids trigger highly protective reflexes, consisting primarily of swallowing and coughing, and aimed at preventing subglottal entrance of potential hazardous material (Thach, 2001). Since the initial observations of Johnson et al. (1972) in anesthetized lambs, over 50 studies have reported that inhibitory cardio-respiratory responses to application of water on the larynx are characteristic of the immature, newborn mammal. In the newborn, LCR are composed of a vagal efferent component, which includes laryngospasm, central or mixed/obstructive apnea, oxygen desaturation and bradycardia, and a sympathetic efferent component,
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which includes systemic hypertension and redistribution of blood flow to vital organs, such as the brain and heart (Thach, 2001). Clinical relevance of LCR stems from the recognition that LCR can be specifically triggered by gastro-esophageal reflux and feeding, and is involved in apparent life-threatening events in infants and possibly in some cases of sudden infant death syndrome (Page and Jeffery, 2000; Thach, 2001). While numerous studies have assessed LCR in response to various liquids in newborn mammals, most were of disputed clinical relevance, due to inherent experimental conditions (use of anesthesia or sedation, instillation of liquids on the tracheal side of the larynx, use of distilled water). In particular, the effects of acid solutions (as a surrogate for gastric liquid) have been much less studied than that of water. This recognition provided us the impetus to engage in a research program on LCR using the full-term and preterm newborn lamb models, whilst focusing on experiments relevant to clinical conditions. 3.1. Laryngeal chemoreflexes in response to acid solutions Findings from a recent study conducted on LCR in non-sedated, full-term lambs during nonREM sleep reveal that instillation of both distilled water and acid solutions elicit very mild cardio-respiratory responses. However, lower airway protective reflexes, including swallowing, cough and arousal, are prominent, especially following acid solutions, suggesting that the latter are more potent stimuli than distilled water (St-Hilaire et al., 2005). Accordingly, results in nonsedated piglets using distilled water yielded similarly mild cardio-respiratory responses, eliciting both swallowing and arousal (Page et al., 1995). Conversely, preliminary findings in preterm lambs have shown much more potent cardio-respiratory responses, including prolonged apneas with oxyhemoglobin desaturation and bradycardia (ongoing experiments). Our findings in lambs also mimic clinical observations in human infants, in whom immature LCR, characterized by prominent cardio-respiratory responses, are mainly observed in preterm infants, or in conditions where upper airway inflammation is present (e.g., respiratory syncytial virus infection) (Lindgren et al., 1992). Laryngeal chemoreflexes elicited by acid solutions (e.g., gastric liquid) warrant further scrutiny, due to
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their clinical relevance (gastro-esophageal reflux). Differences between responses to acids and water are likely related to stimulation of different laryngeal receptors. Two types of water receptors have been described in the laryngeal mucosa, responding either to low chloride concentrations or to hypo-osmolality (Anderson et al., 1990). By comparison, extracellular acidification can alter the activity of several ionic channels, including the vanilloid receptor (VR1), the acidsensitive Na channels (ASIC) and the acid-sensitive K channels (TASK). To our knowledge, while VR1 receptors have been shown to be present in the laryngeal mucosa in adult rats (Yamamoto and Taniguchi, 2005), presence of the ASIC and TASK channels has yet to be confirmed at the laryngeal level. Laryngeal C fiber endings (with VR1 receptors) have been shown to be sensitive to citric acid, but insensitive to water in adult guinea pigs (Forsberg et al., 1988). Similarly, our previous results in lambs suggest that while laryngeal C fibers are functional in the neonatal period, they are insensitive to water (Roulier et al., 2003). Ongoing experiments are currently assessing the possibility of inhibiting acid-triggered LCR by C fiber blockade. 3.2. Modulation of laryngeal chemoreflexes Previous results suggest that the central respiratory drive is a major determinant of the apnea component of the LCR (Lawson, 1982; Van Der Velde et al., 2003). In addition, several studies have studied the possibility of decreasing the immature, prominent cardio-respiratory component of the LCR in the newborn mammal with various drugs. The more notable results can be summarized as follows. The LCR can be blunted by various interventions, including central M3 muscarinic receptor antagonists (Richardson et al., 1997), ß-adrenergic agonists (Grogaard et al., 1986), aminophylline (Lee et al., 1977), antihistamine agents (Downs et al., 1995), acetazolamide (Heman-Ackah and Goding, 2000) and topical lidocaine (McCulloch et al., 1992). In addition, pre-treatment with calcitonin gene-related peptide (CGRP) antagonists also prevents some components of the LCR elicited by water in piglets (Bauman et al., 1999), which suggests that C fibers may be involved in LCR in the newborn. The above results certainly form the basis for further studies aimed at the therapeutic prevention of the cardio-respiratory inhibitory component of the LCR.
In summary, full-term lambs appear to have mature LCR, characterized by lower airway protective mechanisms and absence of clinically significant apneabradycardia. The converse is also true in preterm lambs, which exhibit severe and prolonged apneas, bradycardia and oxyhemoglobin desaturation. Additional studies are needed to further ascertain clinically-relevant conditions known to exacerbate LCR in the full-term infant, including the characterization of the likewise clinically-relevant neuronal mechanisms responsible for LCR triggered by acid solutions.
4. Swallowing and respiration in the newborn With the recent publication of several comprehensive reviews on nutritive swallowing in the newborn (Oommen, 2004; Miller and Kiatchoosakun, 2004), this next section will primarily focus on recent data on non-nutritive swallowing (NNS) and its coordination with breathing in newborns. Swallowing is a vital function throughout life. While protecting lower airways from tracheal aspiration, it fulfils two main objectives. First, nutritive swallowing ensures adequate food intake and normal growth. Secondly, non-nutritive swallowing clears saliva, airway secretions and/or gastric content refluxed into the pharynx. The latter is especially relevant in the newborn, in whom immaturity of the gastro-esophageal junction is responsible for regurgitations in virtually all infants in the first months of life. Since breathing and swallowing are competing functions at the upper airways level, coordination between swallowing and breathing is crucial. Neural immaturity of the newborn, especially in preterms, impairs that coordination (Lau et al., 2003; Mizuno and Ueda, 2003; Oommen, 2004). This may lead to apneas of prematurity, with hypoxemia and bradycardia, as well as to apparent lifethreatening events of infancy, via LCR or tracheal aspiration. 4.1. Swallowing function in the neonatal period Sucking is the first phase of nutritive swallowing in the newborn. Efficient nutritive sucking is lacking prior to 32 weeks postconceptional age (PCA) and reaches a mature pattern at about 36 weeks PCA (Lau et al., 2003; Mizuno and Ueda, 2003; Oommen, 2004). The sec-
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ond swallowing phase, namely the pharyngeal phase, associates closure of the velo-pharyngeal sphincter and the larynx, relaxation of the crico-esophageal sphincter and contraction of the pharynx in order to propel the bolus into the esophagus. Finely coordinated contraction of a number of pharyngeal and laryngeal muscles (approximately 20 pairs of muscles) is crucial during this phase, in order to ensure coordination between competing breathing and swallowing activities. A short (0.6–1 s) obligatory swallowing apnea is present with laryngeal closure. Breathing–swallowing coordination undergoes maturation between 32 and 36 weeks PCA, and rhythmic (mature) breathing during nutritive swallowing is usually established at 36 weeks PCA (Mizuno and Ueda, 2003). Finally, the third swallowing phase, namely the esophageal phase, ensures progression of the bolus towards the stomach. Conversely to nutritive swallowing, non-nutritive swallowing begins with the pharyngeal phase and is triggered by afferent messages in the pharyngeal and the superior laryngeal nerves. Non-nutritive swallowing occurs either as isolated swallows or in bursts. Relevance for addressing NNS and its coordination with breathing initially stems from the fact that NNS is a major component of the mature laryngeal chemoreflexes. In addition, the temporal coincidence between apneas of prematurity and NNS has led to suggest that NNS may cause neonatal apneas (see below). 4.2. Factors influencing the frequency of non-nutritive swallowing 4.2.1. States of alertness In the neonatal period, all known studies but one (Don and Waters, 2003) have reported that NNS frequency is at its highest in REM sleep, and at its lowest in nonREM sleep (Page et al., 1995; Jeffery et al., 2000; Reix et al., 2003a,b, 2004). In fetal and newborn (both preterm and full-term) lambs, NNS bursts are much more frequent in REM sleep (Reix et al., 2003a,b, 2004). These observations are reminiscent of the more rapid and irregular respiration in REM sleep than in NREM sleep and may originate at the level of the swallowing central pattern generator itself. Similarly, the wakefulness stimulus may influence the swallowing central pattern generator, as it does for the respiratory central pattern generator.
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4.2.2. Gestational age While gestational age does not have any effect on the frequency of isolated NNS, the frequency of NNS bursts is higher in preterm than in full-term lambs, regardless of the state of alertness (three to four times higher during wakefulness and REM sleep, and 10 times higher during nonREM sleep) (Reix et al., 2003a,b, 2004). Similar results have been obtained in preterm infants (Pickens et al., 1989; Page et al., 1995). These data have led to speculate that preterm birth leads to an increase in pharyngo-laryngeal sensitivity, which in turn could be responsible for an increased number of swallows for a given stimulus (Pickens et al., 1989). The physiological consequences of these repeated swallows still remain to be proven, some authors considering them as ineffectual (Pickens et al., 1989). 4.2.3. Other potential influences Given the swallowing immaturity of preterm newborns before 36 weeks of postconceptional age, any neonatal condition impacting on NNS activity has theoretically the potential for delaying swallowing maturation and/or leading to prolonged swallowing abnormalities, due to high cerebral plasticity. One example of such sequellae is the marked and prolonged nutritive suck-swallow dysfunction observed in infants following prolonged endotracheal intubation or nasogastric tube feeding initiated in early life (Dello Strologo et al., 1997). One can thus question the consequences of hypercapnia and/or hypoxia, which are very frequent occurrences in preterm newborns, at times for up to several weeks. Current knowledge on the effects of hypoxia on swallowing is restricted to one report concluding that acute hypoxia inhibits swallowing induced by stimulation of the superior laryngeal nerve in decerebrate adult cats (Nishino et al., 1986). With regard to hypercapnia, results are also restricted to acute hypercapnia, which has been shown to decrease waterinduced swallowing in adult humans (Nishino et al., 1998) and to decrease nutritive swallowing frequency in newborns (Timms et al., 1993). To our knowledge, there is no available data on the influence of neonatal hypoxia or hypercapnia on NNS. Many other conditions in the newborn may also, on the long or mean term, impact on swallowing function. Examples of such conditions are the repeated or prolonged use of sedatives or caffeine, for which there are currently no data.
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Similarly, while clinical experience strongly suggests that interventions such as prolonged nasal CPAP or intermittent positive pressure ventilatory support can markedly impact swallowing maturation in the newborn, tangible evidence is still lacking. 4.3. Breathing and swallowing interactions Breathing and swallowing are competing functions at the upper airway level (Oommen, 2004). Interestingly, deglutitive and respiratory central pattern generators are situated in close vicinity to each other in the
brainstem, namely in the regions of the nucleus tractus solitarius and the nucleus ambiguus. This anatomical proximity thereby facilitates both reciprocal inhibition and coordination (Miller and Kiatchoosakun, 2004). 4.3.1. Coordination between swallowing and phases of the respiratory cycle Four types of swallows can be described in relation with their time of occurrence within the respiratory cycle (Fig. 2). They include the e- and i-types (preceded and followed by expiration and inspiration, respectively), and the ei- and ie-types (occurring at the
Fig. 2. (A) i-type NNS (preceded by and followed by inspiration) during quiet sleep; (B) e-type NNS (preceded by and followed by expiration) occurring during active sleep; (C) ie-type NNS (at the phase transition between inspiration and expiration) occurring during quiet sleep; (D) ei-type NNS (at the phase transition between expiration and inspiration) during quiet sleep. Abbreviations: F: nasal airflow, inspiration upward; Dia: raw diaphragmatic EMG signal; ʃDia: integrated diaphragmatic EMG signal; EEG: electroencephalogram; EOG: electrooculogram. See Fig. 1 legend for other abbreviations.
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transition from expiration to inspiration and from inspiration to expiration, respectively). Relevance for the analysis of the fine coordination between NNS and the phases of the respiratory cycle stems from the premise that NNS occurring in inspiration carries a higher risk of aspiration (Lau et al., 2003). Conversely, one could argue that NNS occurring in expiration could carry the risk of stronger inhibition of the respiratory centers, leading to apnea. 4.3.2. Factors influencing non-nutritive swallowing coordination with phases of the respiratory cycle 4.3.2.1. States of alertness. The only data available in the neonatal period are derived from lambs, either fullterm and preterm, and reveal the same pattern of NNS distribution during quiet wakefulness, nonREM sleep and REM sleep (Reix et al., 2003a,b, 2004). Hence, the i-type (40%) represents the most frequent NNS type while the e-type represents the least frequent (less than 10%). 4.3.2.2. Influence of age. The same pattern of NNS distribution was observed in both preterm and full-term lambs, suggesting that gestational age has no influence on fine NNS-breathing coordination at birth. In the preterm infant, NNS have been reported to occur anywhere within the respiratory cycle (Wilson et al., 1981). Longitudinal data on the evolution of the coordination between NNS and respiration does not appear to be available. However, data on nutritive swallowing in humans suggest the existence of postnatal maturation. Indeed, while up to 50% of nutritive swallows are preceded by an inspiration in the newborn (Lau et al., 2003; Mizuno and Ueda, 2003), over 75% of swallows in adult humans are consistently of the e-type (Nishino et al., 1998). In addition, conversely to adult humans, a large proportion (up to 55%) of nutritive swallows in the newborn are preceded and followed by a short apnea, a phenomenon which is more predominant with lower gestational age (Lau et al., 2003; Mizuno and Ueda, 2003). 4.3.2.3. Influence of species and experimental conditions. Data on the coordination between swallowing and the respiratory cycle in adult mammals are conflicting, NNS being described either mostly during inspiration (Feroah et al., 2002), or mostly during expiration
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(Nishino et al., 1998). Species differences, e.g., body position (biped versus quadruped), probably account in part for these observed differences. However, variability of experimental conditions, especially with regard to the technique employed for the induction of swallowing and the use or non-use of sedation/anesthesia, are all likely contributors to the confusion existing in this area. 4.3.3. Apnea and non-nutritive swallowing While NNS have been reported with isolated central, obstructive or mixed apneas in the human newborn (Wilson et al., 1981; Miller and DiFiore, 1995; Don and Waters, 2003; Reix et al., 2004), the majority of apneas associated with NNS are either obstructive or mixed. In the preterm lamb, only 10% of apneas are associated with NNS, mostly during REM sleep (Reix et al., 2004). The mechanisms involved in the association between apneas and NNS remain controversial. While virtually all NNS (either isolated or in bursts) associated with apneas in the preterm lamb occur after onset of apnea, recent data in preterm infants suggest that NNS could trigger up to 25% of apneas (Don and Waters, 2003). Some arguments support the hypothesis of a peripheral origin to this association, while others are supportive of a central origin (Reix et al., 2004). In the peripheral hypothesis, stimulation of chemo- and/or mechanoreceptors at the laryngeal or pharyngeal levels would produce both apneas and swallowing. Alternatively, receptor stimulation by negative pressures developing during obstructive apneas could trigger NNS in REM sleep. In the central hypothesis, NNS occurrence during apneas is likely related to the desinhibition of the swallowing central pattern generator during central inspiratory drive arrest. However, this hypothesis is inconsistent with the higher incidence of NNS during obstructive/mixed apneas, when central inspiratory drive is present. In summary, non-nutritive swallowing, and its relationship with breathing, is an important consideration in understanding respiration in normal and pathological conditions in the newborn. Limited available data suggest the establishment of a precise coordination between NNS and phases of the breathing cycle at birth, even before term. As in the case of apneas, NNS – especially when occurring in bursts – is associated with some obstructive/mixed spontaneous apneas in REM
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sleep, but very rare with periodic breathing in nonREM sleep. 5. Conclusion Consideration of upper airway dynamics is imperative for understanding neonatal respiration in normal and pathological conditions. Available data on neonatal apneas suggest that upper airway closure can occur at various levels in the newborn, including passive pharyngeal collapse and active laryngeal closure. Our findings lead us to propose that the latter can be beneficial in the newborn, by limiting hypoxemia following repetitive central apneas during periodic breathing epochs. In addition, we believe that immaturity of the reflexes originating from the laryngeal chemoreceptors, including laryngeal chemoreflexes and nonnutritive swallowing, contributes to the occurrence of apneas, bradycardia and oxyhemoglobin desaturation in early life, with potentially dramatic consequences. This indubitably underscores the need for additional research in the area of upper airway function and respiration in the neonatal period.
Acknowledgements Jean-Paul Praud is a “national researcher scholar” of the Fonds de la recherche en sant´e du Qu´ebec. This work was supported by the Canadian Institutes of Health Research, grant 15558, and the Quebec Foundation for Research into Children’s Diseases. Studies in preterm lambs were made possible thanks to a gracious donation of BLES surfactant by BLES Inc., London, Ont., Canada.
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J.-P. Praud, P. Reix / Respiratory Physiology & Neurobiology 149 (2005) 131–141 Lindgren, C., Jing, L., Graham, B., Grogaard, J., Sundell, H., 1992. Respiratory syncytial virus infection reinforces reflex apnea in young lambs. Pediatr. Res. 31, 381–385. McCulloch, T.M., Flint, P.W., Richardson, M.A., Bishop, M.J., 1992. Lidocaine effects on the laryngeal chemoreflex, mechanoreflex, and afferent electrical stimulation reflex. Ann. Otol. Rhinol. Laryngol. 101, 583–589. Miller, M.J., DiFiore, J.M., 1995. A comparison of swallowing during apnea and periodic breathing in premature infants. Pediatr. Res. 37, 796–799. Miller, M.J., Kiatchoosakun, P., 2004. Relationship between respiratory control and feeding in the developing infant. Sem. Neonatol. 9, 221–227. Milner, A.D., Greenough, A., 2004. The role of the upper airway in neonatal apnea. Sem. Neonatol. 9, 213–219. Mizuno, K., Ueda, A., 2003. The maturation and coordination of sucking, swallowing, and respiration in preterm infants. J. Pediatr. 142, 36–40. Nishino, T., Kohchi, T., Honda, Y., Shirahata, M., Yonezawa, T., 1986. Differences in the effects of hypercapnia and hypoxia on the swallowing reflex in cats. Br. J. Anaesth. 58, 903– 908. Nishino, T., Hasegawa, R., Ide, T., Isono, S., 1998. Hypercapnia enhances the development of coughing during continuous infusion of water into the pharynx. Am. J. Respir. Crit. Care Med. 157, 815–821. Oommen, M.P., 2004. Respiratory control during oral feeding. In: Oommen, M.P. (Ed.), Respiratory Control and Disorders in the Newborn. Lung Biology in Health and Disease, vol. 173. Marcel Dekker, New York, pp. 373–393. Page, M., Jeffery, H.E., Marks, V., Post, E.J., Wood, A.K., 1995. Mechanisms of airway protection after pharyngeal fluid infusion in healthy sleeping piglets. J. Appl. Physiol. 78, 1942– 1949. Page, M., Jeffery, H., 2000. The role of gastro-oesophageal reflux in the aetiology of SIDS. Early Hum. Dev. 59, 127–149. Pickens, D.L., Schefft, G.L., Thach, B.T., 1989. Pharyngeal fluid clearance and aspiration preventive mechanisms in sleeping infants. J. Appl. Physiol. 66, 1164–1171. Praud, J.-P., Canet, E., Bureau, M.A., 1992. Chemoreceptor and vagal influences on thyroarytenoid muscle activity in awake lambs during hypoxia. J. Appl. Physiol. 72, 962–969. Praud, J.-P., Kianicka, I., Leroux, J.-F., Dalle, D., 1996. Prolonged active glottis closure after barbiturate-induced fatal respiratory arrest in lambs. Respir. Physiol. 104, 221–229.
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Reix, P., Arsenault, J., Dome, V., Fortier, P.-H., Rouillard-Lafond, J., Moreau-Bussi`ere, F., Dorion, D., Praud, J.-P., 2003a. Active glottal closure during central apneas limits oxygen desaturation in premature lambs. J. Appl. Physiol. 94, 1949–1954. Reix, P., Fortier, P.-H., Niyonsenga, T., Arsenault, J., Letourneau, P., Praud, J.-P., 2003b. Non-nutritive swallowing and respiration coordination in full-term newborn lambs. Respir. Physiol. Neurobiol. 134, 209–218. Reix, P., Arsenault, J., Langlois, C., Niyonsenga, T., Praud, J.-P., 2004. Non-nutritive swallowing and respiration relationships in preterm lambs. J. Appl. Physiol. 97, 1283–1290. Renolleau, S., L´etourneau, P., Niyonsenga, T., Praud, J.-P., 1999. Thyroarytenoid muscle electrical activity during spontaneous apneas in preterm lambs. Am. J. Respir. Crit. Care. Med. 159, 1396–1404. Richardson, B.E., Pernell, K.J., Goding Jr., G.S., 1997. Effect of antagonism at central nervous system M3 muscarinic receptors on laryngeal chemoresponse. Ann. Otol. Rhinol. Laryngol. 106, 920–926. Roulier, S., Arsenault, J., Reix, P., Dorion, D., Praud, J.-P., 2003. Effects of C fiber blockade on cardio-respiratory responses to laryngeal stimulation in conscious lambs. Respir. Physiol. Neurobiol. 136, 13–23. St-Hilaire, M., Nsegbe, E., Gagnon-Gervais, K., Samson, N., Moreau-Bussi`ere, F., Fortier, P.-H., Praud, J.-P., 2005. Laryngeal chemoreflexes induced by acid water, and saline in non-sedated newborn lambs during quiet sleep. J. Appl. Physiol., in press. Thach, B.T., 2001. Maturation and transformation of reflexes that protect the laryngeal airway from liquid aspiration from fetal to adult life. Am. J. Med. 111, 69S–77S. Thuot, F., Lemaire, D., Dorion, D., Praud, J.-P., 2001. Active glottal closure during anoxic gasping in lambs. Respir. Physiol. 128, 205–218. Timms, B.J.M., DiFiore, J.M., Martin, R.J., Miller, M.J., 1993. Increased respiratory drive as an inhibitor of oral feeding of preterm infants. J. Pediatr. 123, 127–131. Van Der Velde, L., Curran, A.K., Filiano, J.J., Darnall, R.A., Bartlett Jr., D., Leiter, J.C., 2003. Prolongation of the laryngeal chemoreflex after inhibition of the rostral ventral medulla in piglets: a role in SIDS? J. Appl. Physiol. 94, 1883–1895. Wilson, S.L., Thach, B.T., Brouillette, R.T., Abu-Osba, Y.K., 1981. Coordination of breathing and swallowing in human infants. J. Appl. Physiol. 50, 851–858. Yamamoto, Y., Taniguchi, K., 2005. Immunolocalization of VR1 and VRL1 in rat larynx. Auton. Neurosci. 117, 62–65.
Upper airways and neonatal respiration Jean-Paul Praud a,∗ , Philippe Reix b a
Neonatal Respiratory Research Unit, Departments of Pediatrics and Physiology, Faculty of Medicine, Universit´e de Sherbrooke, Sherbrooke, Que., Canada J1H 5N4 b Department of Pediatrics, Universit´ e de Lyon, France Accepted 30 April 2005
Abstract The upper airways exert an important influence on breathing from the fetal period onward. This review focuses on recent results obtained in the newborn, particularly on laryngeal function in the lamb. Cumulated data can be summarized as follows. Firstly, upper airway closure, either at the pharyngeal or laryngeal level, is now known to occur during central apneas. By maintaining a high apneic lung volume throughout central apneas, active laryngeal closure decreases the magnitude of post-apneic desaturation. Secondly, reflexes originating from laryngeal mucosal receptors, such as laryngeal chemoreflexes and non-nutritive swallowing, are of crucial importance within the context of preterm birth, postnatal maturation, neonatal apneas and apparent life-threatening events/sudden infant death syndrome. While laryngeal chemoreflexes appear to be mature and confer an efficient protection against aspiration in the full-term healthy newborn, they can be responsible for prolonged apneas and bradycardias in the immature preterm newborn. In regard to non-nutritive swallowing, the absence of swallowing activity during apneas in periodic breathing during quiet sleep as well as the presence of bursts of swallows with apneas in active sleep remain to be explained. Forthcoming studies will have to further delineate the impact of common clinical conditions, such as cigarette smoke exposure and/or viral respiratory infection on laryngeal chemoreflexes and non-nutritive swallowing. Better knowledge on the importance of the upper airways in neonatal respiration will ultimately aid in designing clinical applications for the understanding and treatment of severe, pathological respiratory conditions of the newborn. © 2005 Elsevier B.V. All rights reserved. Keywords: Larynx; Apnea; Sleep; Lamb
1. Introduction The upper airways, consisting of the nose, mouth, pharynx and larynx, are an essential component of the ∗ Corresponding author. Tel.: +1 819 346 1110x14851; fax: +1 819 564 5215. E-mail address: [email protected] (J.-P. Praud).
1569-9048/$ – see front matter © 2005 Elsevier B.V. All rights reserved. doi:10.1016/j.resp.2005.04.020
breathing apparatus and exert an important influence on breathing from the fetal period onward. In addition to participating in fetal lung growth, in the establishment and maintenance of optimal end expiratory lung volume at birth and in the decrease in upper airway inspiratory resistance during air breathing, they are also involved in reflex mechanisms such as nutritive and non-nutritive swallowing and cough. A number of
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pathological conditions, such as anatomical abnormalities of the cervico-facial region or central neurological immaturity due to preterm birth, can lead to upper airway dysfunction and obstructed breathing in the newborn. Furthermore, neural immaturity in the newborn is often responsible for reflexes originating from the nose or the laryngeal region, which are inhibitory to cardio-respiratory rhythm. This short review will focus on recent findings on laryngeal function, in relation to neonatal apneas, laryngeal chemoreflexes, and coordination between non-nutritive swallowing and respiration. Importance of these findings is ultimately related to their clinical applications in the understanding and treatment of severe, pathological respiratory conditions of the newborn.
2. Upper airways and apneas in the newborn 2.1. Neonatal apneas Apneas, defined as a breathing pause corresponding to at least “two missed breaths”, are very frequent in the neonatal period, especially in the preterm newborn. Short isolated apneas without bradycardia or decline in oxygenation are especially frequent following sighs and with body movements or arousals. Apneas accompanied by bradycardia or a significant decline in oxygenation, regardless of apnea duration, are regarded as pathological and basically the only apneas of real importance for the clinician. As a whole, neonatal apneas are more common, longer and more frequently associated with severe hypoxemia and bradycardia during rapid eye movement sleep (REM sleep). Three types of apneas have been reported in newborn humans: central, obstructive and mixed. Central apneas occur with greater frequency in nonREM sleep, often as periodic breathing, which is defined as the alternation of central apneas and regular breathing. Apneas become predominantly mixed when they are longer than 10 s. Purely obstructive apneas are much less frequent (Baird, 2004; Milner and Greenough, 2004). Consequences of neonatal apneas on blood gases (hypoxia) and heart rate (bradycardia) can be immediately life-threatening due to severe cerebral hypoxia, especially in preterm infants, and carry the potential of lifelong neurological sequellae, namely
cerebral palsy. While many questions on the mechanisms responsible for controlling neonatal apneas remain unresolved, available data suggest an important role for the upper airways, even during central apneas. 2.2. Upper airways and neonatal apneas Upper airways are of course an essential component of mixed/obstructive apneas. Aside from conditions such as congenital abnormalities (e.g., cervico-facial malformations, laryngomalacia, vocal cord paralysis), it is generally acknowledged that two different mechanisms are involved in mixed/obstructive apneas in the newborn. The most frequently recognized mechanism is passive pharyngeal collapse during inspiration (Milner and Greenough, 2004), which is favored by conditions such as cervical flexion, nose obstruction or lack of pharyngeal muscle-diaphragm coordination secondary to central neural immaturity/abnormalities. In addition, it is well recognized that active glottal closure can occur as part of the laryngeal chemoreflexes, which are triggered by stimulation of laryngeal mucosal receptors by liquids. Laryngeal chemoreflexes in the immature newborn include central or mixed apneas, among other reflexes, and are observed in response to pooling of salivary or respiratory secretions, gastro-esophageal reflux and during feeding (Thach, 2001). Although less often recognized, upper airway closure during central apneas now appears to be frequent in the newborn mammal. Again, passive pharyngeal collapse has been shown to be present during central apneas, both isolated and during periodic breathing epochs (see review, Milner and Greenough, 2004). Several arguments also support the presence of frequent active glottal closure during central apneas in the human newborn. Indeed, endoscopic observation of sustained glottal closure during central apneas has been shown during apneas of prematurity, both isolated and during periodic breathing (Milner and Greenough, 2004), a fact frequently reported by clinicians at laryngoscopy. Several animal studies in the 1980s lent further support to the concept of frequent active glottal closure during central apneas in the newborn mammal, including lambs (Harding, 1986), dog pups (England, 1985) and newborn opossums (Farber, 1972). However, given the paucity of spontaneous apneas observed in newborn mammals born at term
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and the difficulty of documenting glottal closure in human infants, the importance of these observations was not fully recognized. Data from our laboratory obtained in non-sedated lambs have established that the above observations were indeed not just anecdotal. The reader is referred to previous publications from our group for methodological details on glottal muscle EMG recording and methods to induce central apneas in full-term lambs (Renolleau et al., 1999; Fortier et al., 2003). First, in full-term lambs, we were able to show that continuous glottal constrictor EMG (recorded with wire electrodes surgically implanted in the thyroarytenoid muscle) is consistently observed throughout artificiallyinduced central apneas, both isolated and during periodic breathing epochs. Complete active glottal closure was confirmed by recording positive translaryngeal pressure with continuous glottal constrictor EMG throughout induced apneas. In addition, while tracheal pressure was continuously above atmospheric pressure, observation that supra-glottal pressure was consistently atmospheric throughout induced central apneas revealed that the pharynx was not (completely) closed during apneas (Fortier et al., 2003) (Fig. 1). However, in order to establish their physiological rele-
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vance, the above findings needed to be replicated during spontaneous apneas. At first, this latter approach was prevented by the very few spontaneous apneas actually experienced by full-term lambs, even while moving freely, using a custom-designed radio telemetry system (Renolleau et al., 1999). A suitable animal model of neonatal apneas was finally achieved with lambs born prematurely between 129 and 132 days of gestation (term = 147 days) (Renolleau et al., 1999). Since then, characterization of this unique model from 133 to 152 days of postconceptional age has shown that cardiorespiratory immaturity is indeed present. This is manifested by a decrease in the cardio-respiratory response to hypercapnia and hypoxia, as compared to term lambs (unpublished observations), and by numerous spontaneous central apneas, both isolated and within periodic breathing epochs, leading to repetitive drops in oxyhemoglobin saturation, as measured by pulse oximetry (SpO2 ) (Renolleau et al., 1999; Reix et al., 2003a,b). Continuous glottal constrictor EMG was observed in 88% of these central apneas, both isolated and during periodic breathing, ranging from 75% in REM sleep to more than 90% in nonREM sleep and quiet wakefulness. Furthermore, glottal constrictor EMG was consistently associated with positive subglottal pressure and
Fig. 1. Periodic breathing developing at return from a 15-min hypoxic run (FI O2 = 0.08) to room air breathing. TA: raw thyroarytenoid muscle (a glottal constrictor muscle) electrical activity (EMG); ʃTA: moving time averaged TA (time constant: 100 ms); Supra: supra-glottal pressure; Sub: sub-glottal pressure; Flow: nasal flow, inspiration upwards; Sum: variations of lung volume, assessed from respiratory inductance plethysmography.
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maintenance of a high apneic lung volume, i.e., inspiratory breath-holding, throughout spontaneous apneas (Renolleau et al., 1999; Reix et al., 2003a,b). More recently, glottal dilator muscle EMG was shown to be present during only 10–30% of central apneas (in both full-term and preterm lambs), mostly only during the last third of apneas (unpublished observations). Glottal dilator muscle EMG was also shown to be accompanied by a simultaneous decrease in apneic lung volume. 2.3. Consequences of glottal closure throughout neonatal central apneas Consequences of active glottal closure throughout central apneas can be theoretically either beneficial or deleterious and are not fully determined as of yet. Benefits are related to consequences of inspiratory breath-holding, i.e., maintenance of a high lung volume, maintenance of positive sub-glottal pressure and resumption of breathing with expiration. Maintenance of a high pulmonary volume during central apneas increases alveolar O2 stores and limits arterial O2 desaturation, despite absent lung ventilation (Reix et al., 2003a,b). In addition, maintenance of positive sub-glottal pressure likely increases lower airway stability and lung compliance whilst decreasing the tendency for atelectasis and further hypoxemic apnea. Finally, resumption of breathing with expiration can minimize aspiration of secretions, which may have accumulated in the hypopharynx during apnea. Conversely, while one can speculate on the deleterious effects of inspiratory breath-holding in newborns, the importance of such effects remains to be demonstrated. While breathing cessation in an inspiratory position could theoretically inhibit the next inspiration through the Hering–Breuer inhibitory reflex and thereby prolong apnea duration, this has not been supported by our findings (Reix et al., 2003a,b). Finally, while the return of inspiratory efforts despite on-going laryngeal closure (mixed apnea) has been observed in preterm lambs (Renolleau et al., 1999; Reix et al., 2003a,b), it remains a rare occurrence in this model. 2.4. Origin of active glottal closure during neonatal central apneas Interestingly, the above observations of active glottal closure with inspiratory breath-holding throughout
central apneas in newborn lambs have ontogenetic and phylogenetic correlations. From a phylogenetic standpoint, alternation of breathing movements and prolonged apneas, with the exchanger full of gas (i.e., inspiratory breath-holding with active glottal closure), is currently considered to represent the basic breathing pattern in air-breathing vertebrates. This primitivebreathing pattern can be observed to this day in lower vertebrates such as amphibians and aquatic reptiles, and is also present in diving mammals such as whales and seals, even while on land. From an ontogenetic standpoint, during late gestation, “fetal breathing” is present as alternating periods with diaphragm EMG bursts during REM sleep and prolonged “central apneas” with active glottal closure during nonREM sleep. Active glottal closure is responsible for positive pressure in the trachea, which, by distending the liquid-filled airways, is an important mechanism promoting prenatal lung growth. And although active glottal closure during central apneas is usually considered vestigial at most in non-diving adult mammals, it has been reported in adult humans during a few spontaneous central apneas (Insalaco et al., 1993). Finally, inspiratory breath-holding with active glottal closure is commonly observed throughout life with Valsalva maneuvers in conditions such as defecation, micturition, parturition and heavy load carrying. However, contrary to induced apneas in full-term lambs (Kianicka et al., 1998), Valsalva maneuvers are associated with forceful tonic abdominal muscle contraction throughout inspiratory breath-holding. Data in the literature on laryngeal control during apnea are scarce and unclear. Insofar as central mechanisms are concerned, the demonstration that stimulation of ␣2 adrenergic agonists induces tonic glottal constrictor EMG during central apneas in awake goats has led to speculation on the direct involvement of brainstem ␣2 adrenergic receptors in active glottal closure during apneas (Hedrick et al., 1998). This hypothesis still awaits confirmation. As for the effect of peripheral input, investigators have previously speculated that increased vagal afferent activity related to decreased lung volume is responsible for continuous glottal constrictor EMG during central apneas in full-term lambs (Harding, 1986). However, glottal constrictor EMG is still observed throughout induced central apneas in fullterm lambs, despite thoracic vagotomy (Praud et al., 1992) or maintenance of a high lung volume (Praud
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et al., 1996). These observations are also independent of the presence of laryngeal afferent activity, as shown after severing of both superior laryngeal nerves (Fortier et al., 2003). Glottal constrictor EMG is not modified either by various conditions of arterial PO2 or PCO2 (Praud et al., 1992, 1996; Fortier et al., 2003). This demonstrates that neither central nor peripheral chemoreceptor activity is the primary factor responsible for active glottal closure throughout central apneas in full-term lambs. Of interest, active glottal closure is also present throughout inspiratory breath-holding, alternating with gasps during anoxic gasping in lambs (Thuot et al., 2001). Since gasping respiration is speculated to originate from different brainstem centers than those implicating eupnea, such observations suggest that reciprocal inhibition between motoneurons driving glottal constrictor muscles and inspiratory bulbospinal neurons is a consistent feature despite varying respiratory control circumstances, including eupnea, apnea and gasping respiration. In summary, upper airway closure appears to be an important feature of neonatal apneas, including not only during obstructive/mixed apneas, but also during central apneas. Current evidence supports the view that both passive pharyngeal collapse and active glottal closure are involved. The presence of either of these mechanisms may depend on species differences or other, yet undefined, conditions. 3. Laryngeal chemoreflexes The laryngeal chemoreflexes (LCR) are triggered by the contact between liquids – either acid or with low chloride content – and receptors of the laryngeal mucosa in mammals. In a mature organism, liquids trigger highly protective reflexes, consisting primarily of swallowing and coughing, and aimed at preventing subglottal entrance of potential hazardous material (Thach, 2001). Since the initial observations of Johnson et al. (1972) in anesthetized lambs, over 50 studies have reported that inhibitory cardio-respiratory responses to application of water on the larynx are characteristic of the immature, newborn mammal. In the newborn, LCR are composed of a vagal efferent component, which includes laryngospasm, central or mixed/obstructive apnea, oxygen desaturation and bradycardia, and a sympathetic efferent component,
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which includes systemic hypertension and redistribution of blood flow to vital organs, such as the brain and heart (Thach, 2001). Clinical relevance of LCR stems from the recognition that LCR can be specifically triggered by gastro-esophageal reflux and feeding, and is involved in apparent life-threatening events in infants and possibly in some cases of sudden infant death syndrome (Page and Jeffery, 2000; Thach, 2001). While numerous studies have assessed LCR in response to various liquids in newborn mammals, most were of disputed clinical relevance, due to inherent experimental conditions (use of anesthesia or sedation, instillation of liquids on the tracheal side of the larynx, use of distilled water). In particular, the effects of acid solutions (as a surrogate for gastric liquid) have been much less studied than that of water. This recognition provided us the impetus to engage in a research program on LCR using the full-term and preterm newborn lamb models, whilst focusing on experiments relevant to clinical conditions. 3.1. Laryngeal chemoreflexes in response to acid solutions Findings from a recent study conducted on LCR in non-sedated, full-term lambs during nonREM sleep reveal that instillation of both distilled water and acid solutions elicit very mild cardio-respiratory responses. However, lower airway protective reflexes, including swallowing, cough and arousal, are prominent, especially following acid solutions, suggesting that the latter are more potent stimuli than distilled water (St-Hilaire et al., 2005). Accordingly, results in nonsedated piglets using distilled water yielded similarly mild cardio-respiratory responses, eliciting both swallowing and arousal (Page et al., 1995). Conversely, preliminary findings in preterm lambs have shown much more potent cardio-respiratory responses, including prolonged apneas with oxyhemoglobin desaturation and bradycardia (ongoing experiments). Our findings in lambs also mimic clinical observations in human infants, in whom immature LCR, characterized by prominent cardio-respiratory responses, are mainly observed in preterm infants, or in conditions where upper airway inflammation is present (e.g., respiratory syncytial virus infection) (Lindgren et al., 1992). Laryngeal chemoreflexes elicited by acid solutions (e.g., gastric liquid) warrant further scrutiny, due to
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their clinical relevance (gastro-esophageal reflux). Differences between responses to acids and water are likely related to stimulation of different laryngeal receptors. Two types of water receptors have been described in the laryngeal mucosa, responding either to low chloride concentrations or to hypo-osmolality (Anderson et al., 1990). By comparison, extracellular acidification can alter the activity of several ionic channels, including the vanilloid receptor (VR1), the acidsensitive Na channels (ASIC) and the acid-sensitive K channels (TASK). To our knowledge, while VR1 receptors have been shown to be present in the laryngeal mucosa in adult rats (Yamamoto and Taniguchi, 2005), presence of the ASIC and TASK channels has yet to be confirmed at the laryngeal level. Laryngeal C fiber endings (with VR1 receptors) have been shown to be sensitive to citric acid, but insensitive to water in adult guinea pigs (Forsberg et al., 1988). Similarly, our previous results in lambs suggest that while laryngeal C fibers are functional in the neonatal period, they are insensitive to water (Roulier et al., 2003). Ongoing experiments are currently assessing the possibility of inhibiting acid-triggered LCR by C fiber blockade. 3.2. Modulation of laryngeal chemoreflexes Previous results suggest that the central respiratory drive is a major determinant of the apnea component of the LCR (Lawson, 1982; Van Der Velde et al., 2003). In addition, several studies have studied the possibility of decreasing the immature, prominent cardio-respiratory component of the LCR in the newborn mammal with various drugs. The more notable results can be summarized as follows. The LCR can be blunted by various interventions, including central M3 muscarinic receptor antagonists (Richardson et al., 1997), ß-adrenergic agonists (Grogaard et al., 1986), aminophylline (Lee et al., 1977), antihistamine agents (Downs et al., 1995), acetazolamide (Heman-Ackah and Goding, 2000) and topical lidocaine (McCulloch et al., 1992). In addition, pre-treatment with calcitonin gene-related peptide (CGRP) antagonists also prevents some components of the LCR elicited by water in piglets (Bauman et al., 1999), which suggests that C fibers may be involved in LCR in the newborn. The above results certainly form the basis for further studies aimed at the therapeutic prevention of the cardio-respiratory inhibitory component of the LCR.
In summary, full-term lambs appear to have mature LCR, characterized by lower airway protective mechanisms and absence of clinically significant apneabradycardia. The converse is also true in preterm lambs, which exhibit severe and prolonged apneas, bradycardia and oxyhemoglobin desaturation. Additional studies are needed to further ascertain clinically-relevant conditions known to exacerbate LCR in the full-term infant, including the characterization of the likewise clinically-relevant neuronal mechanisms responsible for LCR triggered by acid solutions.
4. Swallowing and respiration in the newborn With the recent publication of several comprehensive reviews on nutritive swallowing in the newborn (Oommen, 2004; Miller and Kiatchoosakun, 2004), this next section will primarily focus on recent data on non-nutritive swallowing (NNS) and its coordination with breathing in newborns. Swallowing is a vital function throughout life. While protecting lower airways from tracheal aspiration, it fulfils two main objectives. First, nutritive swallowing ensures adequate food intake and normal growth. Secondly, non-nutritive swallowing clears saliva, airway secretions and/or gastric content refluxed into the pharynx. The latter is especially relevant in the newborn, in whom immaturity of the gastro-esophageal junction is responsible for regurgitations in virtually all infants in the first months of life. Since breathing and swallowing are competing functions at the upper airways level, coordination between swallowing and breathing is crucial. Neural immaturity of the newborn, especially in preterms, impairs that coordination (Lau et al., 2003; Mizuno and Ueda, 2003; Oommen, 2004). This may lead to apneas of prematurity, with hypoxemia and bradycardia, as well as to apparent lifethreatening events of infancy, via LCR or tracheal aspiration. 4.1. Swallowing function in the neonatal period Sucking is the first phase of nutritive swallowing in the newborn. Efficient nutritive sucking is lacking prior to 32 weeks postconceptional age (PCA) and reaches a mature pattern at about 36 weeks PCA (Lau et al., 2003; Mizuno and Ueda, 2003; Oommen, 2004). The sec-
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ond swallowing phase, namely the pharyngeal phase, associates closure of the velo-pharyngeal sphincter and the larynx, relaxation of the crico-esophageal sphincter and contraction of the pharynx in order to propel the bolus into the esophagus. Finely coordinated contraction of a number of pharyngeal and laryngeal muscles (approximately 20 pairs of muscles) is crucial during this phase, in order to ensure coordination between competing breathing and swallowing activities. A short (0.6–1 s) obligatory swallowing apnea is present with laryngeal closure. Breathing–swallowing coordination undergoes maturation between 32 and 36 weeks PCA, and rhythmic (mature) breathing during nutritive swallowing is usually established at 36 weeks PCA (Mizuno and Ueda, 2003). Finally, the third swallowing phase, namely the esophageal phase, ensures progression of the bolus towards the stomach. Conversely to nutritive swallowing, non-nutritive swallowing begins with the pharyngeal phase and is triggered by afferent messages in the pharyngeal and the superior laryngeal nerves. Non-nutritive swallowing occurs either as isolated swallows or in bursts. Relevance for addressing NNS and its coordination with breathing initially stems from the fact that NNS is a major component of the mature laryngeal chemoreflexes. In addition, the temporal coincidence between apneas of prematurity and NNS has led to suggest that NNS may cause neonatal apneas (see below). 4.2. Factors influencing the frequency of non-nutritive swallowing 4.2.1. States of alertness In the neonatal period, all known studies but one (Don and Waters, 2003) have reported that NNS frequency is at its highest in REM sleep, and at its lowest in nonREM sleep (Page et al., 1995; Jeffery et al., 2000; Reix et al., 2003a,b, 2004). In fetal and newborn (both preterm and full-term) lambs, NNS bursts are much more frequent in REM sleep (Reix et al., 2003a,b, 2004). These observations are reminiscent of the more rapid and irregular respiration in REM sleep than in NREM sleep and may originate at the level of the swallowing central pattern generator itself. Similarly, the wakefulness stimulus may influence the swallowing central pattern generator, as it does for the respiratory central pattern generator.
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4.2.2. Gestational age While gestational age does not have any effect on the frequency of isolated NNS, the frequency of NNS bursts is higher in preterm than in full-term lambs, regardless of the state of alertness (three to four times higher during wakefulness and REM sleep, and 10 times higher during nonREM sleep) (Reix et al., 2003a,b, 2004). Similar results have been obtained in preterm infants (Pickens et al., 1989; Page et al., 1995). These data have led to speculate that preterm birth leads to an increase in pharyngo-laryngeal sensitivity, which in turn could be responsible for an increased number of swallows for a given stimulus (Pickens et al., 1989). The physiological consequences of these repeated swallows still remain to be proven, some authors considering them as ineffectual (Pickens et al., 1989). 4.2.3. Other potential influences Given the swallowing immaturity of preterm newborns before 36 weeks of postconceptional age, any neonatal condition impacting on NNS activity has theoretically the potential for delaying swallowing maturation and/or leading to prolonged swallowing abnormalities, due to high cerebral plasticity. One example of such sequellae is the marked and prolonged nutritive suck-swallow dysfunction observed in infants following prolonged endotracheal intubation or nasogastric tube feeding initiated in early life (Dello Strologo et al., 1997). One can thus question the consequences of hypercapnia and/or hypoxia, which are very frequent occurrences in preterm newborns, at times for up to several weeks. Current knowledge on the effects of hypoxia on swallowing is restricted to one report concluding that acute hypoxia inhibits swallowing induced by stimulation of the superior laryngeal nerve in decerebrate adult cats (Nishino et al., 1986). With regard to hypercapnia, results are also restricted to acute hypercapnia, which has been shown to decrease waterinduced swallowing in adult humans (Nishino et al., 1998) and to decrease nutritive swallowing frequency in newborns (Timms et al., 1993). To our knowledge, there is no available data on the influence of neonatal hypoxia or hypercapnia on NNS. Many other conditions in the newborn may also, on the long or mean term, impact on swallowing function. Examples of such conditions are the repeated or prolonged use of sedatives or caffeine, for which there are currently no data.
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Similarly, while clinical experience strongly suggests that interventions such as prolonged nasal CPAP or intermittent positive pressure ventilatory support can markedly impact swallowing maturation in the newborn, tangible evidence is still lacking. 4.3. Breathing and swallowing interactions Breathing and swallowing are competing functions at the upper airway level (Oommen, 2004). Interestingly, deglutitive and respiratory central pattern generators are situated in close vicinity to each other in the
brainstem, namely in the regions of the nucleus tractus solitarius and the nucleus ambiguus. This anatomical proximity thereby facilitates both reciprocal inhibition and coordination (Miller and Kiatchoosakun, 2004). 4.3.1. Coordination between swallowing and phases of the respiratory cycle Four types of swallows can be described in relation with their time of occurrence within the respiratory cycle (Fig. 2). They include the e- and i-types (preceded and followed by expiration and inspiration, respectively), and the ei- and ie-types (occurring at the
Fig. 2. (A) i-type NNS (preceded by and followed by inspiration) during quiet sleep; (B) e-type NNS (preceded by and followed by expiration) occurring during active sleep; (C) ie-type NNS (at the phase transition between inspiration and expiration) occurring during quiet sleep; (D) ei-type NNS (at the phase transition between expiration and inspiration) during quiet sleep. Abbreviations: F: nasal airflow, inspiration upward; Dia: raw diaphragmatic EMG signal; ʃDia: integrated diaphragmatic EMG signal; EEG: electroencephalogram; EOG: electrooculogram. See Fig. 1 legend for other abbreviations.
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transition from expiration to inspiration and from inspiration to expiration, respectively). Relevance for the analysis of the fine coordination between NNS and the phases of the respiratory cycle stems from the premise that NNS occurring in inspiration carries a higher risk of aspiration (Lau et al., 2003). Conversely, one could argue that NNS occurring in expiration could carry the risk of stronger inhibition of the respiratory centers, leading to apnea. 4.3.2. Factors influencing non-nutritive swallowing coordination with phases of the respiratory cycle 4.3.2.1. States of alertness. The only data available in the neonatal period are derived from lambs, either fullterm and preterm, and reveal the same pattern of NNS distribution during quiet wakefulness, nonREM sleep and REM sleep (Reix et al., 2003a,b, 2004). Hence, the i-type (40%) represents the most frequent NNS type while the e-type represents the least frequent (less than 10%). 4.3.2.2. Influence of age. The same pattern of NNS distribution was observed in both preterm and full-term lambs, suggesting that gestational age has no influence on fine NNS-breathing coordination at birth. In the preterm infant, NNS have been reported to occur anywhere within the respiratory cycle (Wilson et al., 1981). Longitudinal data on the evolution of the coordination between NNS and respiration does not appear to be available. However, data on nutritive swallowing in humans suggest the existence of postnatal maturation. Indeed, while up to 50% of nutritive swallows are preceded by an inspiration in the newborn (Lau et al., 2003; Mizuno and Ueda, 2003), over 75% of swallows in adult humans are consistently of the e-type (Nishino et al., 1998). In addition, conversely to adult humans, a large proportion (up to 55%) of nutritive swallows in the newborn are preceded and followed by a short apnea, a phenomenon which is more predominant with lower gestational age (Lau et al., 2003; Mizuno and Ueda, 2003). 4.3.2.3. Influence of species and experimental conditions. Data on the coordination between swallowing and the respiratory cycle in adult mammals are conflicting, NNS being described either mostly during inspiration (Feroah et al., 2002), or mostly during expiration
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(Nishino et al., 1998). Species differences, e.g., body position (biped versus quadruped), probably account in part for these observed differences. However, variability of experimental conditions, especially with regard to the technique employed for the induction of swallowing and the use or non-use of sedation/anesthesia, are all likely contributors to the confusion existing in this area. 4.3.3. Apnea and non-nutritive swallowing While NNS have been reported with isolated central, obstructive or mixed apneas in the human newborn (Wilson et al., 1981; Miller and DiFiore, 1995; Don and Waters, 2003; Reix et al., 2004), the majority of apneas associated with NNS are either obstructive or mixed. In the preterm lamb, only 10% of apneas are associated with NNS, mostly during REM sleep (Reix et al., 2004). The mechanisms involved in the association between apneas and NNS remain controversial. While virtually all NNS (either isolated or in bursts) associated with apneas in the preterm lamb occur after onset of apnea, recent data in preterm infants suggest that NNS could trigger up to 25% of apneas (Don and Waters, 2003). Some arguments support the hypothesis of a peripheral origin to this association, while others are supportive of a central origin (Reix et al., 2004). In the peripheral hypothesis, stimulation of chemo- and/or mechanoreceptors at the laryngeal or pharyngeal levels would produce both apneas and swallowing. Alternatively, receptor stimulation by negative pressures developing during obstructive apneas could trigger NNS in REM sleep. In the central hypothesis, NNS occurrence during apneas is likely related to the desinhibition of the swallowing central pattern generator during central inspiratory drive arrest. However, this hypothesis is inconsistent with the higher incidence of NNS during obstructive/mixed apneas, when central inspiratory drive is present. In summary, non-nutritive swallowing, and its relationship with breathing, is an important consideration in understanding respiration in normal and pathological conditions in the newborn. Limited available data suggest the establishment of a precise coordination between NNS and phases of the breathing cycle at birth, even before term. As in the case of apneas, NNS – especially when occurring in bursts – is associated with some obstructive/mixed spontaneous apneas in REM
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sleep, but very rare with periodic breathing in nonREM sleep. 5. Conclusion Consideration of upper airway dynamics is imperative for understanding neonatal respiration in normal and pathological conditions. Available data on neonatal apneas suggest that upper airway closure can occur at various levels in the newborn, including passive pharyngeal collapse and active laryngeal closure. Our findings lead us to propose that the latter can be beneficial in the newborn, by limiting hypoxemia following repetitive central apneas during periodic breathing epochs. In addition, we believe that immaturity of the reflexes originating from the laryngeal chemoreceptors, including laryngeal chemoreflexes and nonnutritive swallowing, contributes to the occurrence of apneas, bradycardia and oxyhemoglobin desaturation in early life, with potentially dramatic consequences. This indubitably underscores the need for additional research in the area of upper airway function and respiration in the neonatal period.
Acknowledgements Jean-Paul Praud is a “national researcher scholar” of the Fonds de la recherche en sant´e du Qu´ebec. This work was supported by the Canadian Institutes of Health Research, grant 15558, and the Quebec Foundation for Research into Children’s Diseases. Studies in preterm lambs were made possible thanks to a gracious donation of BLES surfactant by BLES Inc., London, Ont., Canada.
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